Breast cancer is the leading site of new cancer cases in women, and the second leading cause of death. Considerable progress has been made in determining the events in the initiation and early development of breast cancer. However, relatively little is known about the molecular basis of metastasis, the primary cause of death from this cancer. Tumor progression to the metastatic state involves important interactions between the tumor cell and its environment. To understand these interactions it has become clear that a more complete knowledge of normal mammary gland development is also required. Recently, we have shown that macrophages are recruited to the stroma surrounding the developing mammary epithelium and infiltrate into mammary tumors. Using mouse mutants that deplete the number of macrophages owing to a null mutation in the gene for major growth factor for macrophages, Colony Stimulating Factor-1 (CSF-1), we found that these cells are required both for mammary development and for tumor progression to the metastatic state. These data suggest that many of the processes, modulated by macrophages that are required for the outgrowth of normal epithelium through the fat pad, are recapitulated during tumor invasion although some functions will be unique to the tumor. The current application aims to understand the mechanistic basis of the macrophage functions that promoting metastasis and normal mammary development. It also aims to identify the means whereby alteration of the stromal compartment potentiates tumor progression to the metastatic state. The specific aims are: 1) Role of CSF-1 regulated macrophages in mammary gland development and tumor progression to metastasis, 2) The mechanistic basis of the role of macrophages in mammary development and tumor cell motility, invasion and metastasis. 3) Isolation of novel genes that have a role in the macrophage action on mammary gland development and tumor invasion and metastasis. In humans, over-expression of CSF-1 and CSF-1R in tumors of the breast is associated with poor prognosis. Our studies suggest that CSF-1 regulates a population of macrophages that play an important role in tumor progression to the metastatic state. Understanding the mechanistic basis of the macrophage enhancement of metastasis could result in the development of novel therapeutics aimed at preventing this step.